Neural Circuit Disruption in Freely-Behaving models of Alzheimer's Disease.

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Background Summary/Abstract Determining how A and tau degrade neural systems function in Alzheimer’s disease remains an essential objective. Although much has been learned from models of early onset Alzheimer’s disease (EOAD), including demonstration of aberrant neuronal activity and calcium overload in anesthetized amyloid models, the generalizability of these observations depends on two major caveats: First, it is not clear how findings under anesthesia extrapolate, particularly as the effects of amyloid and tau appear to depend on behavioral state. Second, it is not clear whether findings in EOAD models will inform understanding of late onset Alzheimer’s disease (LOAD), which is far more common and arises in association with multiple genetic risk factors. To address these issues, we will apply and integrate a series of new technologies. To extend studies to freely behaving animals and determine the behavioral state-dependence of A’s impact on neuronal physiology, we will employ the Inscopix mini-microscope to monitor calcium activity together with concomitant multi-electrode recordings to assess brain oscillations. To extend studies to LOAD, we study and contrast the APP/PS1 model of EOAD with the new hAbeta.ApoE4.Trem2*R47H model of LOAD. This model, which includes knock-in of the humanized APP gene in concert with the strong risk variants APOE (humanized ApoE4) and TREM2*R47H, develops elevated levels of A42 and A40. To evaluate tau’s contribution to neuronal dysfunction and its interactions with A in these amyloid models, we employ an AAV vector that expresses equimolar levels of human tau and GCaMP6f, enabling dynamic calcium imaging in tau-laden cells with the mini-microscope. To evaluate how the development of tau aggregates interacts with amyloid to affect neuronal physiology, we combine mini-microscope imaging of dynamic calcium activity with 2-photon imaging of tangles and plaques. We hypothesize that in both APP/PS1 (to model EOAD) and hAbeta.ApoE4.Trem2*R47H (to model LOAD), A and tau will be associated with behavioral state-dependent changes in neuronal activity, brain oscillations, and calcium overload; that tau’s state-dependent effects will dominate those of A in the EOAD and LOAD models; and that the development of tau aggregates will synergistically interact with amyloid to degrade neuronal activity. Together, these efforts will establish how A and tau impair neural systems function, advancing Alzheimer’s disease modeling and informing therapeutic development.